5446
J . A m . Chem. SOC.1987, 109, 5446-5452
the solvent evaporated. The residue was applied to half of an analytical each molecule was chosen according to t h e guidelines set forth TLC plate (20 X 20 cm) and eluted twice with 2:l:l hexane-CH2CI2in the M A C R O M O D E L documentation. In each case, the closure ether. The minor, fast-moving band (RJ0.47, 1 mg) corresponded to bond was chosen to be the bond between the third and fourth independently synthesized keto lactone D7. The major band (4.9 mg, atoms away from the lactone carbonyl carbon. In the case of 44%) was isolated as the diastereomeric dithioketal: NMR (270 MHz, 2,3-dimethylcyclododecene,the bond between the fourth and fifth CDCI3) 6 5.05 (d of quartets, J = 6.2, 2.3 Hz, 1 H), 4.90 (ddd, J = 10.1, atoms away from the unsubstituted alkene carbon was chosen. 4.5,2.3Hz,1H),3.27(m,4H),2.50(ddd,J=14.4,6.4,4.1Hz,1H), The closure distance was varied between 1.0 and 2.0 8, to generate 2.24 (ddd, J = 4.0, 11.3, 14.4 Hz, 1 H), 2.13 (s, 3 H), 1.89-1.76 (m, 12 between 500 and 800 conformations a s suggested by the M A H), 1.22 (d, J = 6 Hz, 2 H); IR (CCI,) 2970, 1745 cm-'; m / e , calcd for C R O M O D E L documentation. These values were highly deC16H2604S2 346.12723, found 346.1271. The sample was recrystallized from hexane at -25 OC, mp 136-139 OC. pendent on the structure of the molecule. For example, for Epoxidation; Elimination of 6 . The epoxidation, DBU sequence as structure 5Z 822 starting conformations were generated with a described for 5E starting with 17 mg of 6 gave a mixture of two products, minimum closure distance of 1.0 8, and a maximum closure separable by TLC (50% ethyl acetate-hexane). The more polar band (RJ distance of 1.85 8,. T h e torsional angle defined by the lactone 0.1) was 21 (3.4 mg, 18%): IR (neat) 3580 (w), 2930, 1730, 1690, 1640 subunit was constrained to be 180' in all cases. In the case of cm-I;NMR (270 MHz, CDC13) 6 6.56 ( d , J = 15.8 Hz, 1 H), 6.42 (d, the cycloalkenes, the angle defined by the double bond was conJ = 15.8 Hz,1 H), 4.90 (dd, J = 9.5, 4.0 Hz, 1 H), 2.66 (ddd, J = 12.5, trained to be 0 ' or 180°, depending upon its cis or trans nature. 7.0, 6.3 Hz, 1 H), 2.50 (ddd, J = 3.0, 11.5, 14.5 Hz, 1 H), 2.33 (m, 2 For the epoxides studied, the torsional angle defined by the epoxide H), 2.00-1.40 (m, 11 H), 1.34 (s, 3 H), 0.92 (t, J = 7.3 Hz, 3 H); m / e , was allowed to assume four angles. For the epoxides derived from calcd for C14H2204 254.2247, found 254.2247. The sample crystallized on standing and was recrystallized (hexane/CH2CI2)giving white neethe cis alkenes, the angles were -40, -20, 0, and 20'; for the trans dles, mp 141-143 OC. The faster moving band (Rf0.15) proved to be epoxides the angles were 140, 160, 180, and 200'. All other the diastereomeric lactone 20'' (5.5 mg, 29%), identical with an authentic torsional angles were permitted to freely rotate within the 60' sample provided by Prof. M. Yamaguchi. resolution constraints. Default values were used for all other Osmylation of 6. The same procedure used for JE converted 6 (24 parameters in the Multiconformer routine. mg) into a crude hydroxy enone mixture. The less polar product (6.4 mg, 23%) again corresponded to the Yamaguchi lactone 20 while the more Acknowledgment. This work was supported by the National polar isomer was 21 (9.7 mg, 36%). Science Foundation (CHE-8306121) and, in part, by a n N I H Appendix postdoctoral fellowship to W.D. (GM.11546). T h e N I H instruMACROMODEL Parameters. The structures found in Figures ment grant ( R R O 2388-01) used to obtain the AM-500 M H z 1-4 were minimized with use of the Multiconformer routine in N M R spectrometer is also acknowledged. Special thanks are due M A C R O M O D E L using the default values of 60' dihedral angle to Prof. W . C. Still for providing the M A C R O M O D E L program resolution and 10' bond angle resolution. T h e closure bond for used in the computations.
An Asymmetric Synthesis of (-)-Steganone. Further Application of Chiral Biaryl Syntheses A. I. Meyers,* Joseph R. Flisak, and R. Alan Aitken Contribution f r o m the Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523. Received February 5, 1987
Abstract: An asymmetric synthesis of the title compound has been achieved by initially forming an axially chiral biphenyl precursor l l a mediated by a chiral aromatic oxazoline (+)-lo. The eight-membered ring was constructed around the biphenyl with particular attention addressing the rotational barrier for biphenyls to avoid racemization. The efficiency of this total synthesis was quite good until the last step, which incorporates the lactone moiety. Furthermore, approximately 10% racemization occurred in one of the latter steps (17-18) which was not evident until the final target was reached.
W e have shown in previous reports that a n aromatic system containing a chiral oxazoline is capable of being coupled with aromatic Grignard or lithium reagents furnishing chiral biphenyls,' binaphthyls,2 and related ~ y s t e m s . ~W e now describe the total synthesis of (-)-steganone (1) which originates from a diastereoselective coupling of two aryl moieties furnishing the axially chiral biphenyl required to construct the target compound (Scheme 1). (-)-Steganone (l),a n antileukemic bisbenzocyclooctadiene lignan lactone, one of four isolated from Steganotaenia araliacea by Kupchan in 1973: has attracted considerable synthetic interest. These lignans have demonstrated significant in vivo activity against
pr
Scheme I 0
Me0
Me0
Ph
OM9
1 OMe
(1) Meyers, A. I.; Hirnrnelsbach, R. J. J . Am. Chem. SOC.1985,107, 682. (2) Meyers, A. I.; Lutornski, K.A. J . Am. Chem. SOC.1982, 204, 879. (3) Meyers, A. I.; Wettlaufer, D. G. J . Am. Chem. SOC.1984, 106, 1135. (4) Kupchan, S.M.; Britton, R. W.; Ziegler, M. F.; Gilrnore, c. J.; Restive, R. J.; Bryan, R. F . J . Am. Chem. SOC.1973, 95, 1 3 3 5 .
0002-7863/87/ 1509-5446$01.50/0
P-388 leukemia in mice and have displayed significant in vitro activity against derived from human carcinoma Of the nasopharynx (KB). T h e natural product contains three Stereochemical elements, two of which a r e on the lactone ring and the
0 1987 American Chemical Society
An Asymmetric Synthesis of (-)-Steganone
J . Am. Chem. SOC..Vol. 109, No. 18, 1987 5447
Scheme I1
r?
r?
I-?
i
CHO
CHO
Scheme 111 Br
OMe
r---l--
10
9
10
9
Figure 1. Aldehyde signal of l l c : (a) immediately after isolation; (b) after 4 days at 25 OC. Scheme IV
+ OYe Me0
Me0 OM9
(*).la
I
Q
third is the asymmetric biaryl bond between the two phenyl rings. T o date there have been a total of nine successful syntheses of steganone. Six of these are syntheses of (=t)-steganone5 and three have been enantioselective syntheses of (-)-steganone.6 Of the latter three syntheses, Raphael's6b employs a resolution step while the remaining two arrive a t the natural product from a lactone fragment of known absolute stereochemistry derived from Lglutamic acid.6a,c T h e strategy of the past enantioselective syntheses was to initially synthesize the two stereocenters of the lactone ring and subsequently form the asymmetric biaryl bond. Thus, the axial asymmetry of the biaryl bond was induced by the two asymmetric centers on the lactone. T h e novel feature of the present approach, based on earlier studies from this laboratory,'-3 was to initially form the axially chiral biaryl system, containing the requisite functional groups, in addition to the proper substituents to avoid aryl-aryl bond rotation. T h e failure to hinder bond rotation would result in racemization and therefore preclude any acquisition of chiral, nonracemic product. The retrosynthetic plan, as shown Scheme I, was therefore inaugurated, which required preparation of the upper and lower fragments. The coupling of the Grignard reagent by displacing the o-methoxyl to the chiral oxazoline was anticipated to proceed with some degree of axial diastereoselectivity. T h e upper portion of 4 was readily prepared from piperonal 2 by bromination to o-bromopiperonal3,' followed by acetalization with 1,3-propanediol. The lower portion of (+)-lo was also prepared by using a series of well-precedented steps. Thus, bromination* of commercially available 3,4,5-trimethoxybenzoic acid gave the 2-bromo derivative 6 and treatment with NaOMe-Cu9 displaced the bromine furnishing the tetramethoxybenzoic acid 7. T h e latter was transformed into the amide (oxalyl chloride, N H J and after treatment
OMe
I+).Lp
with triethyloxonium fluoroborate it gave the imidate 8. As previously described,I0 the imidate was stirred with (1S,2S)(+)-l-phenyl-2-amino-3-methoxy-l-propanol (9) producing the completed lower portion of 10. The overall yield of (+)-lo was 67% based on the benzoic acid 7. With the two precursors for the biaryl coupling in hand, the next stage of our effort was to generate the Grignard reagent of 4, and this was performed by using the entrainment method." Addition of 4 to 3 equiv of magnesium in T H F followed by 2 equiv of 1,2-dibromoethane gave the corresponding Grignard reagent in quantitiative yield. Addition of 0.7 equiv of the (tetramethoxypheny1)oxazoline 10 and refluxing ( T H F ) overnight furnished the biaryl coupling products lla and llb in 85% yield as a 7 : l mixture of diastereomers (NMR)." Flash chromatography cleanly separated lla (65% yield) and llb (9% yield). At this juncture, assignment of the major diastereomer to lla and the minor to llb was purely arbitrary. This assumption, however, proved to be correct as the synthesis reached its final target. With a pure diastereomer lla in hand, it was now necessary to unmask the functionality to elaborate the biaryl to the 8-membered ring (10) Meyers, A. I.; Knaus, G.;Kamata, K.; Ford, M. E. J . Am. Chem. SOC.
(5) (a) Magnus, P.; Schultz, J.; Gallagher, T. J . Am. Chem. SOC.1985, 107, 4984. (b) Dhal, R.; Robin, J. P.; Brown, E. Tetrahedron 1983, 39, 2787. (c) Mervic, M.; Ben-David, Y . ;Ghera, E. Tetrahedron Lett. 1981, 22, 5091. (d) Ziegler, F. E.; Chliwner, I . C.; Fowler, K. W.; Kanfer, S. J.; Kuo, S. J.; Sinha, N. D. J . Am. Chem. SOC.1980, 102, 790. (e) Brown, E.; Dhal, R.; Robin, J. P. Tetrahedron Lett. 1979, 733. (0Larson, E. R.; Raphael, R. A. Tetrahedron Lett. 1979, 5041. (9) Becker, D.; Hughes, L. R.; Raphael, R. A. J . Chem. SOC.,Perkin Trans. 1 1977, 1674. (h) Hughes, L. R.; Raphael, R. A. Tetrahedron L e f t . 1976, 1543. (i) Kende, A. S.; Liebeskind, L. S. J . Am. Chem. SOC.1976, 98, 267. (6) (a) Tomioka, K.; Ishiguro, T.; Iitaka, Y . ;Koga, K. Tetrahedron 1984, 40, 1303. (b) Larson, E. R.; Raphael, R. A. J . Chem. SOC.,Perkin Trans. 1 1982, 521. (c) Robin, J. P.; Gringgore, 0.;Brown, E. Tetrahedron L e t f . 1980, 2704. (7) Becker, D.; Hughes, L. R.; Raphael, R. A. J . Chem. SOC.,Perkin Trans. 1 1977, 1674. (8) Mayer, W.; Fikentschen, R. Chem. Ber. 1956, 89, 511. (9) Mayer, W.; Fikentschen, R. Chem. Ber. 1958, 91, 1536.
1916, 98, 561.
(1 1) Lai, Y . H. Synthesis 1981, 585. (12) The original plan of the synthesis involved the dithiane derivative A and coupling to the (tetramethoxyphenyl)oxazoline, 10. This process proceeded to give B in 60% yield, isolated as a single diasteromer. However, all
OMe
A
B
attempts to metalate the dithiane and introduce the methyl group met with failure. No deprotonation was observed on B with a wide range of bases and reaction conditions.
5448 J . Am. Chem. SOC.,Vol. 109, No. 18, 1987 Scheme V
Meyers et al.
Scheme VI 7-0
OMe
L3
‘OM0
A
present in steganone. This series of manipulations required that conditions be found to avoid rotation of the aryl-aryl bond, and therefore avoid epimerization. T h e first transformation t o be addressed involved removal of the acetal in l l a affording the aldehyde l l c . I t had previously been observed’ that a n sp2 substituent ( H C O ) ortho to the biaryl linkage reuslts in aryl-aryl bond rotation. However, the presence of the bulky oxazoline a t the other ortho position should raise the barrier to bond rotation and allow l l c to have some reasonable half-life. With this under consideration, the acetal was smoothly cleaved with 3 N HCI-THF a t room temperature. Examination of the N M R spectrum of the resulting aldehyde (270 M H z ) revealed that the pure diasteromer of acetal l l a had given rise to two aldehydes in the ratio 7:1, indicating that under these hydrolytic conditions, some epimerization (aryl-aryl bond rotation) had occurred. Repeating the hydrolysis (3 N HCI-THF) a t 0 OC gave the aldehyde l l c in a 15:l ratio, thus much improved over the earlier hydrolysis (Figure 1). A stability study was performed by monitoring the 15:l mixture of 11 by N M R and observing the changes in the formyl proton over time. After 4 days a t 25 O C , the mixture had reached equilibrium (Figure Ib). Thus, bond rotation in the biaryl system was indeed a problem to be reckoned with, although proceeding rather slowly. Finally, the cleavage of l l a to l l c was performed a t -5 OC with the HCI-THF mixture and workup carried out a t 0 OC, including solvent evaporation. Under these conditions, no trace of the epimer of l l c could be detected when its N M R spectrum was taken immediately after isolation. Since the next step in the synthesis involved addition of methylmagnesium bromide to the aldehyde and the resulting secondary alcohol should, with its sp3 nature, be stable to bond rotation, a protocol was invoked which required that the immediately isolated aldehyde l l c be rapidly treated with the Grignard reagent. In this fashion 12 was formed in 92% yield as 1:l diastereomeric mixture of secondary alcohols. This mixture was cleanly separated by flash chromatography, and each diasteromer of 12 was completely characterized. Thus, if any aryl-aryl bond rotation had occurred during the acetal hydrolysis or the methylmagnesium bromide addition, it would have been easily detected by examining their respective N M R spectra. Furthermore, each diasteromeric secondary alcohol of 12 could be used in the synthetic route since a t a later stage in the synthesis this alcohol function was to be oxidized to a methyl ketone (vide infra). These epimers of 12 were also found to be completely stable to aryl-aryl bond rotation even when heated to reflux as a toluene solution. Each diasteromer of 12 was carried forward separately until they converged to the same compound (17), and both gave 19 which was characterized as being identical from both series (12a 19; 12b 19). Protection of the respective secondary alcohols (12a, 12b) was accomplished by transforming them into their allyl ethers (13a, 13b) with sodium hydride and allyl iodide. A t this point in the synthetic scheme, the chiral oxazoline was removed and once again concern arose that the conditions for removal had to be compatible with the rotational barrier of the aryl-aryl bond. T h e method of choice of oxazoline removal involved treatment of 13(a or b) with a slurry of sodium bisulfate-water in T H F for 3-4 h, which protonated the oxazoline nitrogen. After 40-48 h the ring slowly opened to the amino ester sulfate salt (A). Isolation was performed with acidic media followed by reduction of A with lithium aluminum hydride to afford the alcohol 14(a or b). If the ester A was exposed to neutral or alkaline conditions during the workup, rearrangement to the amide B became a serious side reaction (see Experimental Section). In fact, if water was present during the hydride reduction, the LizO produced caused the rearrangement (A B) to occur very rapidly and the amide was the only product obtained. The resulting benzyl alcohols 14a,b were not sufficiently
- -
-
,-0
OMe
Ma a) NES b) &(C02MBIp
OM0
OMe
1pLEs1, R i CH(OH)CH, v. R.C-CH,
b 1&
m 15p
R,C-CH2Bf I,
0
stable to allow complete characterization, and thus they were transformed quickly to the bromide with N-bromosuccinimidetriphenylphosphine, which were directly converted to the malonate esters 15a,b under the usual malonate ion substitution conditions. In this fashion, 15(a or b) was obtained pure and characterized. The yield of 15 was 56-61%, based on the oxazoline 13(a or b). With the successful removal of the chiral oxazoline performed under unusually mild conditions and each diasteromer 15a and 15b apparently devoid of any aryl-aryl bond rotation (via N M R ) , it was now necessary to remove the allyl protecting group. This was readily done by rhodium-catalyzed is~merization’~ to the vinyl ether followed by hydrolytic cleavage catalyzed by mercuric chloridemercuric oxide.I4 In this manner, each diasteromer 16a,b was obtained in 83% yield. T h e latter were stable products and showed no signs of aryl-aryl bond rotation. This is to be expected since both ortho positions contained sp3-bonded substituents which inhibited bond rotation. The alcohols 16 were individually oxidized to the methyl ketone 17 with pyridinium chlorochromate, and in view of the sp2 substituent now present, it was immediately brominated with pyridinium bromide perbromide in trifluoroacetic acid, according to Ziegler.5d The resulting a-bromo ketone 18 was also presumed to be a racemizable intermediate, capable of allowing aryl-aryl bond rotation, and thus it, too, was treated without delay with potassium tert-butoxide to afford the cyclic ketone 19, in an overall yield of 54% from the alcohol 16. At this point it is noteworthy to mention again that each diastereomer, individually, from 12 gave 19, which confirmed that the only difference in their stereochemistry arose from the secondary alcohol on the “top” half of the biaryl system. T h e remainder of the synthetic scheme now relied completely on the ZieglerSdsynthesis of racemic steganone. Thus, the cyclic ketone 19, combined from both individual diastereomeric sequences, was treated with potassium hydroxide to produce the dicarboxylic acid, which was thermally decarboxylated to the monocarboxylic acid and esterified to the methyl esters 20 and 21. However, this sequence led to a conformational mixture (1:l) of the biphenyl system. Each (20 and 21) could be easily separated by flash chromatography to give pure 20 and 21 which were individually characterized. However, the undesired conformer, which is stable a t ambient temperature, is known to intercovnert upon heating.5d*fJ5 Thus, 21 was heated in xylene and gave 20 and 21 again as a 1:l mixture of rotamers. This mixture was again separated, and the thermal interconversion was repeated several times. In this manner, >90% of the appropriate isomer 20 was readily obtained. (13) Gent, P. A,; Gigg, R. Chem. Commun. 1974, 277. (14) Gigg, R.; Warren, C. D. J . Chem. Sac. C 1968, 1903. ( 1 5 ) Kende, A. S.; Liebeskind, L. S.; Kubiak, C.; Eisenberg, R. J . Am. Chem. SOC.1976, 98, 6389.
J . A m . Chem. Soc., Vol. 109, No. 18, 1987 5449
A n Asymmetric Synthesis of (-)-Steganone Scheme VI1
Scheme VI11 I-0
Y O
Y O
t-BuOe
18 CO,Me Me0
Me0 C0,Me
Me0
Me0
Me0
,
OMe
17
1La f-0
0 1
1
MeowH MeowH
I O ' $ q a) H,CO b) Jones
t
Me0
C0,Me
C0,Me
Me0
OMe
Me0
OMe
Br Me0
Me0 OMe
OMe
Ub
I&
2 l (50%)
22 (50%)
t
2
crude product recrystallized with 95% ethanol. A second crop of crystals was isolated from the mother liqueur by addition of 50 mL of water. The solution was filtered and the crude product recrystallized from 95% T h e final step in this synthetic effort was performed by inethanol. Combination of the two crops of crystals afforded 44.5g (54%) troducing the hydroxymethyl group a to the ketone in 20 followed of 3 as white needles: mp 131-132 "C (lit.' mp 131 "C); IR (CHCI,) by Jones' oxidation to give (-)-steganone in a disappointing yield 3030,3010,2980,2900,1672,1610,1600,1465,1390,1240,1202,1102, 1028 cm-I; ' H N M R (270 MHz, CDC1,) 6 10.17(1 H,s), 7.35( 1 H, of 11%. This poor conversion of the ketone 20 into (-)-steganone s), 7.05(1 H, s), 6.09(2 H, s); I3C N M R (67.9MHz, CDCI,) 6 190.16, has already been observed by previous worker^.^^,',^ Several at153.48,148.40,128.52,121S O , 1 13.46,108.38,102.89. tempts to improve this step met with failure. l-[l-(2-Bromo-4,S-methylenedioxyphenyl)]-l,3-dioxane (4). A solution Comparison of (-)-1 to the literature values reported by Koga of 12.0g (52.4mmol) of 6-bromopiperonal (3),4.2mL (58.1mmol) of ( [ a ] -191°),6a ~ Kupchan ([DID -2132'),~ and Raphael ( [ a ] ~ 1,3-propanediol,and 200 mg (1.05mmol) of p-toluenesulfonic acid in 100 -197°)6b showed a meaningful discrepancy. The synthetic material mL of benzene was heated under reflux with azeotropic removal of water (-)-1 obtained in this study exhibited [ a ] D -161' in the same (Dean-Stark trap) for 4 h. The solution was cooled to ambient temsolvent and a t the same concentration, while all the other physical perature, washed with water (50mL), and dried (MgSO,) and the soldata were in excellent agreement (mp, N M R ) . However, the vent evaporated to give light orange crystals. Recrystallization from ethyl acetate produced 13.1 g (87%) of 4 as white crystals: mp 94-95 "C; IR specific rotation (-161') possessed by the product indicated a n (CCI,) 3005,2965,2945,2915,2880,2840,1498,1476, 1460,1415, optical purity of 8 0 4 4 % when compared with Koga's and Kup1369,1238,1140,1 1 12,1091,1032,995,930cm-'; ' H NMR (270MHz, chan's values. Furthermore, an authentic sample was obtained16 CDCI3) 6 7.17(1 H, s), 6.96(1 H, s ) , 5.96 (2 H,s), 5.68(1 H, s), 4.24 which in direct comparison with the sample from the present study (2 H, ddd, J = 10.7,5.0,1.2Hz), 4.00(2 H, td, J = 12.2,2.5Hz), 2.21 verified that (-)-I had an [ a ] D about 30' too low. Convinced (1 H, complex m),1.43(1 H, d of heptets, J = 13.4,1.3 Hz): "C NMR that our rotation was indeed indicative of approximately 10% of (67.9MHz, CDIC,) 6 148.87,147.71,131.69,113.30,112.56,108.43, (+)-steganone in the product, the only meaningful conclusion that 101.94,101.09,67.63(2 C), 25.93.Anal. Calcd for Cl,HllBr: C, 46.02; could be drawn is that some racemization (aryl-aryl bond rotation) H, 3.86;Br, 27.83.Found: C, 46.19;H, 3.81;Br, 27.88. had taken place in the last stages of the synthesis involving 17 2-Bromo-3,4,5-trimethoxybenzoic Acid (6). To a stirred refluxing solution of 24.2g (1 14 mmol) of 3,4,5-trimethoxybenzoic acid (S), 2.5 or 18. Since no complete physical characterization was performed mL of water, and 240 mL of chloroform was added a solution of 5.9m L for these two labile intermediates, the P C C oxidation of the (1 15 mmol) of bromine in 50 mL of chloroform. Following addition the carbinol 16 which gave ketone 17 can be assumed to proceed resultant red solution was refluxed for 18 h and then cooled to ambient without aryl bond rotation; however, the bromination step to 18 temperature. The solution was washed with water (2 X 100 mL), dried undoubtedly proceeds via the enol 17a, and it is felt that rotation (MgSO,), and filtered and the solvent evaporated to afford 32.0g (96%) to 1% was the stage at which racemization occurred. It is unlikely of 6 as a light orange solid which was used without further purification: that the 10-12% racemization occurred a t the stage where the mp 147-148 "C (lit.9 mp 149-150 "C); IR (CHCI,) 3500-2600,3030. eight-membered ring was already in place (e.g., 19), thus pre3010,2970,2940,1725,1700,1585,1560,1487,1465,1450,1385,1200, cluding any racemization in the decarboxylation step (19 20). 1160,1105,1000 cm-I; ' H N M R (270MHz, CDC1,) 6 11.60( 1 H, br s), 7.42(1 H, s), 3.98(1 H, s), 3.92(1 H, s), 3.91(1 H, s); I3C NMR On the other hand, it is possible that the racemization had occurred (67.9MHz, CDCI,) 6 170.87,152.36,151.83,147.22,125.67,111.61, during the ring closure involving the a-bromo ketone and the 110.93,61.19,61.03,56.42.Anal. Calcd for CloHl,OjBr: C, 41.26;H, malonate ion (18 19). There was no way for this rotation to 3.81;Br, 27.45. Found: C, 41.37;H, 3.77;Br, 27.39. be detected until the final product was reached and the specific 2,3,4,S-TetramethoxybenzoicAcid (7). To a stirred solution of 7.3g rotations compared to optically pure steganone. Therefore, if the (317mmol) of Na metal dissolved in 380 mL of anhydrous methanol was bromination or cyclization were to be repeated under milder acid (6). added 31.0g (106rnmol) of 2-bromo-3,4,5-trimethoxybenzoic conditions, this racemization, amounting to lo%, could possibly Once the acid had dissolved, 3.0g (47 mmol) of Cu powder was added be avoided. and the mixture refluxed for 18 h. The mixture was cooled, filtered through a bed of Celite, and concentrated in vacuo to give a crude white Experimental Section solid. This was dissolved in 400 mL of water and acidified to pH 3 with 6-Bromopiperonsl(3). To a stirred solution of 55.0g (0.36mmol) of concentrated HCI. The solution was extracted with methylene chloride piperonal (2) in 120 mL of acetic acid was added 21 mL (0.41mmol) (2 X 300 mL), dried (MgS04),filtered, and concentrated to produce a light orange oil. Recrystallization [hexane:ethyl acetate (5:l)] yielded of bromine. The resultant dark red solution was stirred for 18 h after which a red precipitate was present. The solution was filtered and the 23.3 g (90%) of 7 as white prisms: mp 87-88 'C (lit.9 mp 87-88 "C); IR (CCI,) 3400-3100,3060,2995,2935,2830,1743,1685,1485,1462, 1409,1370,1332,1110,1060,845 cm-'; ' H N M R (270 MHz, CDCI,) (16) We thank Professor K. Koga for this sample of (-)-steganone ([ala 6 11.16(1 H, br s), 7.41(1 H , s), 4.09(3 H,s), 3.99(3 H,s), 3.94(3 -191"). H, s), 3.90(3 H, s); I3C N M R (67.9MHz, CDCI,) 6 165.63,149.97, (-)-I
A
-
-
5450
J. Am. Chem. Soc., Vol. 109, No. 18, 1987
148.14, 147.76, 146.39, 116.26, 109.54, 62.46, 61.29,61.08, 56.34. Anal. Calcd for CllH140,: C, 54.54; H, 5.82. Found: C, 54.39; H, 5.77. (+)-2-(2,3,4,5-Tetramethoxyphenyl)-4(S)-(methoxymethyl)-5(S)phenyl-2-oxazoline (10). To a stirred solution of 18.4 g (76.0 mmol) of 2,3,4,5-tetramethoxybenzoicacid (7) dissolved in 350 mL of dry methylene chloride was added 13.4 mL (154 mmol) oxalyl chloride. The yellow solution was stirred overnight at room temperature, the solvent evaporated, and the yellow solid dissolved in 60 mL of diethyl ether. To this stirred solution was added an excess of 30% ",OH which caused a white precipitate to form. This was dissolved in methylene chloride (300 mL), washed with water (100 mL), dried (MgSO,), filtered, and concentrated to afford a white solid. Recrystallization from ethyl acetate produced 17.3 g (94%) of the benzamide as white crystals: mp 121-122 "C; IR (CC14) 3390, 3180, 2990, 2970, 2940, 2830, 1645, 1490, 1465, 1400, 1315, 1215, 1115, 949, 845, 658 cm-l; ' H NMR (270 MHz, CDCI,) 6 7.96 (1 H, br s), 7.46 (1 H, s), 6.75 (1 H, br s), 3.94 (3 H, s), 3.93 (6 H, s), 3.90 (3 H, s); "C NMR (67.9 MHz, CDCI,) 6 166.64, 149.46, 146.91, 146.60, 146.49, 120.01, 108.72, 61.45, 60.97, 60.77, 56.10. Anal. Calcd for CllH150SN:C, 54.77; H, 6.27; N, 5.81. Found: C, 54.60; H, 6.28; N , 5.69. A solution of 10.0 g (41.5 mmol) of 2,3,4,5-tetramethoxybenzamideand 8.2 g (43.1 mmol) of triethyloxonium tetrafluoroborate in 100 mL dry 1,2-dichloroethane under an argon atmosphere was stirred at room temperature for 24 h. To the light yellow solution was added 7.8 g (43.1 mmol) of (lS,2S)-(+)-l-phenyI2-amino-3-methoxy-I-propanol [(+)-9]1°and the resultant dark yellow solution refluxed for 48 h. The solution was cooled to ambient temperature, washed with aqueous Na2C03 (50 mL) and water (2 X 50 mL), dried (MgSO,), filtered, and concentrated in vacuo to afford a dark yellow oil which was purified by Kugelrohr distillation to afford 13.2 g (82%) of 10 as a pale yellow oil: bp 240-250 "C (0.05 Torr); [ a ] 5 8 9 +73.7" (c 2.9, THF); IR (film) 3060, 3030, 2980, 2930, 2890, 2825, 1645, 1595, 1575, 1492, 1463, 1410, 1115, 1063, 795,745,698 cm-'; ' H NMR (270 MHz, CDCI,) 6 7.42-7.33 (5 H, m),7.15 (1 H, s), 5.50 (1 H, d, J = 6.6 Hz), 4.32 (1 H, ddd, J = 9.7, 6.5, 4.5 Hz), 3.95 (3 H, s), 3.94 (3 H , s), 3.87 (3 H , s), 3.86 (3 H, s), 3.77 (1 H, dd, J = 9.7, 4.3 Hz), 3.62 (1 H, dd, J = 9.6, 6.7 Hz), 3.45 (3 H, s); "C NMR (67.9 MHz, CDC13) 6 162.57, 149.14, 148.08, 147.61, 146.07, 141.16, 128.48, 127.89, 127.73, 125.30, 116.58, 108.75, 83.39,74.82, 74.50, 61.45, 60.92, 60.76, 58.91, 56.22. Anal. Calcd for C2,H,,O6N: C, 65.10; H, 6.50; N, 3.62. Found: C, 64.82; H, 6.69; N, 3.61. Biphenyl Oxazolines l l a and l l b . To a stirred mixture of 720 mg (29.6 mmol) of Mg metal in 10 mL of dry T H F under an argon atmosphere was added a solution of 2.58 g (8.99 mmol) of l-[l-[(2-bromo4,5-methylenedioxyphenyl)]-l,3-dioxane(4) in 25 mL of anhydrous THF. The mixture was heated to reflux and then a solution of 1.77 mL (20.6 mmol) of 1,2-dibromoethane in 5 mL of dry T H F was slowly added (ca. 2.5 h). The dark yellow solution was refluxed for 1 h and cooled to ambient temperature, and then 2.37 g (6.11 mmol) of oxazoline 10 in 5 mL of dry T H F was added to the yellow mixture and the solution heated to reflux. The dark yellow-brown solution was refluxed overnight, cooled, and then poured into 25 mL of saturated NH4CI. The layers were separated and the organic layer washed with water (25 mL) and brine (25 mL), dried (MgSO,), filtered, and evaporated to afford a dark yellow-brown oil. Flash chromatography (ethyl acetate) afforded the major diastereomer l l a (RJ0.30, ethyl acetate) which was recrystallized from ethyl acetate to yield 2.24 g (65%) of light yellow prisms and 373 mg (9%) of the minor diasteromer l l b (RJ0.19, ethyl acetate) as a light yellow glass. Major diastereomer l l a : mp 164-165 "C; [a],,, +33.5 (c 2.7, THF); IR (CCI4) 3060, 3030, 2990, 2950, 2925, 2885, 2870, 2840, 2340, 2318, 1640, 1588, 1555, 1497, 1480, 1460, 1420, 1410, 1368, 1332, 1232, 1125, 1104, 1035, 860, 686 cm-'; ' H NMR (270 MHz, CDCL,) 6 7.32-7.20 (4 H, m), 7.17 (1 H, s), 7.11-7.07 (2 H, m), 6.66 (1 H, s), 5.93 (1 H, d, J = 1.4 Hz), 5.91 (1 H, d, J = 1.4 Hz), 5.07 (1 H, s), 5.02 (1 H, d, J = 7.6 Hz), 4.17-3.87 (5 H, complex m) on which is superimposed 3.97 (3 H, s) and 3.94 (3 H, s), 3.73-3.54 ( 1 H, complex m) on which is superimposed 3.61 (3 H, s), 3.46-3.34 (1 H , m) on which is superimposed 3.38(3H,s),2.19-2.01 (1 H,complexm), 1 . 2 6 ( 1 H , b r d , J = 13.3Hz); I3C NMR (67.9 MHz, CDCI,) 6 164.47, 152.42, 151.89, 146.71, 144.49, 140.38, 131.16, 128.89, 128.10, 127.41, 125.19, 123.61, 110.13, 108.70, 105.91, 100.67, 99.81, 84.07, 74.56, 73.76, 66.80, 60.44, 60.34, 58.70, 55.90, 25.41. Anal. Calcd for C31H3409N:C, 66.06; H, 5.90; N, 2.48. Found: C, 66.06; H, 5.91; N, 2.35. Minor diastereomer l l b : [ a ] 5 8+100.9" 9 (c 2.7, THF); IR (CCI,) 3060, 3030,2990,2960,2930,2890, 2870,2850,2340, 1645, 1587, 1557, 1495, 1480, 1460, 1420, 1409, 1368, 1233, 1120, 1102, 1035, 858, 685 cm-I; 'H NMR (270 MHz, CDCI,) 6 7.28-7.17 (4 H, m), 6.99-6.95 (3 H, m), 6.66 (1 H , s), 5.93 (1 H, d, J = 1.4 Hz), 5.83 (1 H, d, J = 1.4 Hz), 5.13 (1 H, d, J = 7.6 Hz), 5.04 (1 H, s), 4.13-3.85 (5 H, complex m) on which is superimposed 3.97 (3 H, s) and 3.94 (3 H, s), 3.72-3.47
Meyers et al.
(2 H, complex m) on which is superimposed 3.61 (3 H, s), 3.37 (3 H , s) 2.17-1.99 (1 H, complex m), 1.24 (1 H, br d, J = 13.2 Hz); I3CNMR (67.9 MHz, CDCIS) 6 164.41, 152.52, 151.99, 146.92, 146.81, 144.37, 140.27, 131.16, 128.68, 128.05, 127.46, 127.09, 125.57, 124.19, 110.45, 108.55, 106.17, 100.67, 99.82, 84.18, 74.27, 66.94, 66.75, 60.55, 60.45, 58.81, 55.96, 25.45. Biphenyl Carbinol Oxazolines 12a and 12b. To a stirred solution of 3.37 g (5.98 mmol) of the biaryl oxazoline l l a in 50 mL of T H F at -5 "C (cooling bath temperature) was sowly added (ca. 0.5 h) 20 mL of 3 N HCI. The resultant yellow solution was stirred for 2.5 h and then poured into a cold (ca. 0 "C) solution of saturated NaHCO, (50 mL) and this mixture extracted with cold (ca. 0 "C) ether (2 X 50 mL). The combined organic layers were washed with cold (ca. 0 "C) brine (50 mL), dried over MgSO, at 0 "C, filtered, and concentrated on a rotary evaporator at 0 "C. The yellow residue was cooled to -78 "C (dry iceacetone) and 50 mL of anhydrous T H F added. To the stirred solution was slowly added (ca. 5 min) an excess of methylmagnesium bromide (5 mL of 2.9 M in ether) and the resultant yellow mixture stirred for 1 h at -78 'C and then allowed to slowly warm to ambient temperature (ca. 5 h). The reaction was quenched with 10 mL of saturated NH,Cl, poured into water (50 mL), and extracted with ether (2 X 50 mL). The combined organic layers were washed with brine (50 mL), dried (MgSO,), filtered, and evaporated to afford a crude yellow oil which was a mixture of diasteromers (1: 1, NMR). Flash chromatography (ethyl acetate) afforded 1.45 g (47%) of 12a (RJ0.3 I , ethyl acetate) and 1.39 g (45%) of 12b ( R ~ 0 . 2 0ethyl , acetate). Diastereomer 12a: mp 145-146 "C; [a]5s9 +88.2' ( e 1.7, THF); IR (CHCI,) 3600-3100, 3070, 3030, 3010,2980, 2940, 2900, 2840, 1655, 1595, 1505, 1485, 1460, 1402, 1351, 1240, 1130, 1108, 1038, 980,938 cm-'; 'H NMR (270 MHz, CDCI,) 6 7.40-7.20 (5 H, m), 7.07 (1 H, s), 7.05 (1 H, s), 6.49 (1 H, s), 5.96 (1 H, d, J = 1.4 Hz), 5.95 (1 H , d,J=1.4Hz),5.23(1H,d,J=6.3Hz),5.17(1H,brs,exchanges with D20), 4.62 (1 H, q, J = 6.4 Hz), 4.14-4.08 (1 H, complex m), 3.94 (3 H, s), 3.92 (3 H, s), 3.68 (3 H, s), 3.28-3.22 ( 1 H, apparent dd, J = ca. 13.8, 9.7 Hz) on which is superimposed 3.25 (3 H, s), 3.05 (1 H, dd, J = 9.7, 6.4 Hz), 1.40 (3 H, d, J = 6.4 Hz); "C NMR (67.9 MHz, CDCI,) 6 164.52, 153.05, 152.12, 147.77, 146.23, 144.86, 140.52, 139.15, 128.89, 128.43, 125.67, 123.62, 109.34, 108.61, 105.58, 101.04, 83.60, 74.08, 73.82, 66.26, 60.98, 59.07, 56.45, 21.89. Anal. Calcd for C,,H,,O,N: C, 66.91; H, 5.81; N, 2.69. Found: C, 66.74; H, 6.02; N, 2.64. Diastereomer 12b: mp 153-154 "C; [ a ] 5 8+49.0° 9 (c 2.2, THF); IR (CHCI,) 3600-3300,3060,3010,2970,2940, 2890, 2820, 1650, 1590, 1560, 1503, 1480, 1460, 1401, 1348, 1230, 1200, 1120, 1102, 1035,975, 931 cm-'; 'H NMR (270 MHz, CDCI,) 6 7.30-7.21 (4 H , m), 7.04 (1 H, s), 6.80-6.76 (2 H, m), 6.57 (1 H, s), 5.96 (1 H, d, J = 1.4 Hz), 5.91 (1 H , d, J = 1.4 Hz), 5.23 (1 H, d, J = 7.4 Hz), 4.60 (1 H, q, J = 6.4 Hz), 4.22-4.11 (1 H, complex m), 3.96 (3 H , s), 3.95 (3 H, s), 3.64 (1 H , dd, J = 9.7, 4.4 Hz), 3.55 (3 H , s), 3.49 (1 H, dd, J = 9.7, 6.4 Hz), 3.40 (3 H, s), 3.02 (1 H, br s, exchanges with D20), 1.26 (3 H , d, J = 6.4 Hz); I3CNMR (67.9 MHz, CDCI,) 6 164.78, 164.63, 152.79, 151.04, 147.71, 146.29, 144.60, 140.42, 138.73, 128.31, 127.82, 127.73, 125.78, 125.41, 124.19, 110.07, 109.97, 105.75, 100.95, 84.07, 74.56, 74.14, 67.37, 61.08, 60.98, 60.82, 59.13, 56.28, 22.32. Anal. Calcd for C29H3108N:C, 66.91; H, 5.81; N, 2.69. Found: C, 66.87; H, 6.13; N , 2.53. Biphenyl Allyl Ether Oxazolines 13a and 13b. To a stirred suspension of 130 mg (5.44 mmol) of NaH in 25 mL of anhydrous T H F under an argon atmosphere was added 1.24 g (2.39 mmol) of the biaryl alcohol 12a (R,0.31, ethyl acetate) in 10 mL of anhydrous T H F at room temperature. The yellow suspension was stirred for 0.5 h and then 0.50 mL (5.46 mmol) of distilled allyl iodide was added and allowed to stir for 18 h. The yellow suspension was cautiously poured into 10 mL water and extracted with ether (2 X 50 mL). The combined organic layers were washed with brine (50 mL), dried (MgSO,), filtered, and evaporated to afford a dark yellow oil that was flash chromatographed (ethyl acetate) to afford 1.15 g (85%) of 13a (RJ0.37, ethyl acetate) as a light yellow +84.3" ( e 1.9; THF); IR (film) 3060, 3000, 2970, 2930, 2890, oil: [a]5s9 2830, 1640, 1590, 1475, 1395, 1365, 1345, 1230, 1120, 1100, 1035,920, 745 crn-l; 'H KMR (270 MHz, CDCI,) 6 7.31 (1 H, s), 7.27-724 (3 H, m), 6.99 (1 H, s), 6.96-6.92 (2 H, m), 6.62 (1 H, s), 5.95 ( I H, d, J = 1.4 Hz), 5.92 (1 H , d, J = 1.4 Hz), 5.77-5.62 (1 H complex m), 5.14 (1 H, d, J = 7.5 Hz), 4.99-4.96 (1 H , m),4.93-4.92 (1 H, m). 4.14 (2 H, apparent q, J = ca. 6.3 Hz), 3.97 (3 H, s), 3.94 (3 H, s), 3.64-3.50 (3 H , complex m) on which is superimposed 3.56 (3 H, s), 3.45 ( I H, dd, J = 9.7, 6.5 Hz), 3.38 (3 H, s ) , 1.34 (3 H , d, J = 6.3 Hz); "C-NMR (67.9 MHz, CDCI,) 6 164.26, 152.53, 147.49, 145.76, 140.31, 137.61, 135.65, 128.28, 128.04, 127.74, 125.46, 123.18, 115.21, 109.87, 109.70, 105.38, 100.73, 84.02, 77.41, 74.35, 74.19, 69.11, 60.68, 60.62, 59.02, 56.10, 23.08.
An Asymmetric Synthesis of (-)-Steganone Similar treatment of 1.23 g (2.36 mmol) of biaryl alcohol 12b (R, 0.20, ethyl acetate) as described for 13a afforded 1.21 g (91%) of 13b (R,0.48, ethyl acetate) as a light yellow oil: [a]589 +30.6' ( c 1.90, THF); IR (film) 3060, 3030, 3010, 2970, 2930, 2890, 2830, 1735, 1642, 1590, 1560, 1475, 1455, 1420, 1400, 1365, 1345, 1230, 1115, 1033,920,862, 745, 690 cm-'; 'H N M R (270 MHz, CDCI,) 6 7.33-7.18 (4 H, m). 7.05 ( 1 H, s), 6.92-6.86 (2 H, m) 6.57 (1 H, s), 5.97-5.83 (1 H, complex m) on which is superimposed 5.96 ( 1 H, d, J = 1.4 Hz) and 5.86 ( 1 H, d, J = 1.4 Hz), 5.28-5.06 (3 H , complex m), 4.25 (1 H, q, J = 6.4 Hz), 4.17-4.10 (1 H, m),3.95-3.85 (2 H, complex m) on which is superimposed 3.95 (3 H, s) and 3.94 (3 H, s), 3.63 (1 H , dd, J = 9.7, 4.4 Hz), 3.56 (3 H, s), 3.47 (1 H , d d , J = 9.7,6.5 Hz), 3.39 (3 H, s), 1.19 (3 H, d, J = 6.4 Hz); "C NMR (67.9 MHz, CDCI,) 6 164.28, 152.62, 150.82, 147.50, 145.84, 144.64, 140.37, 137.71, 135.81, 128.20, 127.96, 127.57, 125.24, 124.13, 115.12, 110.10, 109.79, 105.22, 100.67, 83.85, 77.41, 74.40, 74.07, 68.96, 60.68, 60.49, 58.95, 56.05, 23.13. Biphenyl Carbinols 14a and 14b. To a stirred solution of 1.047 g (1.87 mmol) of biaryl oxazoline 13a (R,0.37, ethyl acetate) in 50 mL of T H F under an argon atmosphere at room temperature was added 5.0 g of powdered NaHSO,.H,O. The resultant yellow mixture was stirred for 3 h and then 25 mL of water was added and the yellow mixture stirred for 48 h at ambient temperature. The two layers were separated and the organic layer washed with saturated brine (2 X 20 mL) adjusted to pH 2. The organic layer was dried briefly over MgSO,, filtered, and then quickly added (ca. IO min) to a stirred mixture of 710 mg (18.7 mmol) of LiAlH, in 50 mL of anhydrous T H F under argon at 0 'C. The reaction mixture was cautiously quenched with water and extracted with dichloromethane (2 X 100 mL). The combined organic layers were washed with brine (50 mL), dried (MgSO,), filtered, and evaporated to afford a yellow oil. This was used immediately for the next step. Malonates 15a and 15b. The product from above was dissolved in 50 mL of dry methylene chloride and then 525 mg (2.00 mmol) of triphenylphosphine was added to the stirred solution. The resultant yellow solution was cooled to 0 OC and a solution of 356 mg (2.00 mmol) of N-bromosuccinimide in 50 mL of dry dichloromethane was added and the solution stirred for 1.5 h at 0 "C. The dark yellow solution was poured into 20 mL of water and the layers separated. The aqueous layer was extracted with dichloromethane (50 mL) and the combined organic layers were washed with brine (50 mL), dried (MgSO,), filtered, and evaporated to afford a dark yellow oil. This was filtered through a 4411. silica plug [hexane:ethyl acetate (1:1)] and evaporated to afford 637 mg (73%) of the crude bromomethyl biphenyl. The latter was dissolved in 5 mL of anhydrous methanol and added to a stirred solution of 500 mg (21.7 mmol) of Na metal and 905 mg (6.85 mmol) of dimethyl malonate in 15 mL of anhydrous methanol. The resultant orange solution was stirred for 1 h, acidified with concentrated HCI, and then poured into 20 mL of water. This was extracted with dichloromethane (2 X 100 mL), and the combined organic layers were washed with brine (50 mL), dried (MgSO,), filtered and evaporated to afford a yellow oil that was flash chromatographed [hexane:ethyl acetate (1:1)] to afford 588 mg (61%) of 15a [R, 0.52, hexane:ethyl acetate (1:1)] as a colorless oil: [ a ] 5 8 9 +27.8' (c 2.2, THF); IR (film) 3080, 3000, 2970, 2950, 2930, 2900, 2840, 1750, 1732. 1592, 1565, 1492, 1478, 1452, 1430, 1398, 1340, 1318, 1230, 1135, 1100, 1030, 922, 745 cm-'; ' H N M R (270 MHz, CDCI,) 6 7.09 ( 1 H, s), 6.56 (2 H , s), 6.02 (1 H, d, J = 1.4 Hz), 5.99 ( 1 H, d, J = 1.4 Hz), 5.93-5.78 ( 1 H, complex m), 5.27-5.25 (1 H, m),5.21-5.18 (1 H, m), 4.02 ( I H, q, J =6.3 Hz), 3.95-3.81 (1 H, complex m) on which is superimposed 3.87 (3 H, s) and 3.86 (3 H, s), 3.76-3.60 ( 1 H, complex m) on which is superimposed 3.66 (3 H , s) and 3.64 (3 H, s), 3.55(1H,apparentdd,J=ca.8.2,7.3Hz),2.96(1H,d,J=8.2Hz), 2.94 ( 1 H, d, J = 7.3 Hz), 1.26 (3 H, d, J = 6.3 Hz); I3C N M R (67.9 MHz, CDCI,) 6 169.17, 168.91, 152.73, 151.89, 147.60, 146.29, 141.10, 136.88, 135.18, 131.34, 127.62, 126.88, 1 15.84, 109.92, 108.28, 105.79, 100.99, 74.24, 69.22, 60.71, 60.57, 55.90, 52.20, 32.11, 22.39. Similar treatment of 1.50 g (2.67 mmol) of the biaryl oxazoline 13b as described for 13a afforded 771 mg (56%) of 15b as a light yellow glass [R,0.58 hexane:ethyl acetate ( l : l ) ] : [cy]5898.8' (c 1.4, THF); IR (film) 3900, 3010, 2970, 2950,2930,2900,2840, 1755, 1735, 1595, 1568, 1500, 1480, 1455, 1434, 1402, 1343, 1230, 1138, 1095, 1032, 995, 923 cm-'; ' H N M R (270 MHz, CDCI,) 6 7.09 (1 H, s), 6.55 (1 H , s), 6.54 (1 H , s ) , 6.02 ( 1 H, d, J = 1.3 Hz), 6.00 (1 H, d, J = 1.3 Hz), 5.91-5.77 (1 H, complex m), 5.24-5.16 (1 H, m), 5.08-5.03 (1 H, m), 4.06 (1 H, q, J = 6.4 Hz), 3.95-3.80 (1 H, m) on which is superimposed 3.86 (6 H, s), 3.76-3.54 (2 H, m) on which is superimposed 3.68 (3 H , s) and 3.67 (3 H, s) and 3.62 (3 H, s), 2.94 (1 H, dd, J = 14.5, 9.0 Hz), 2.76 ( I H , dd, J = 14.5, 6.6 Hz) 1.20 (3 H, d, J = 6.4 Hz); I3C N M R (67.9 MHz, CDCI3) 6 169.06, 168.75, 152.89, 150.94, 147.66, 146.28, 141.26, 137.24, 135.61, 132.12, 127.89, 127.04, 115.21, 109.86, 108.28, 105.85, 100.93, 73.59, 68.96, 60.52, 55.95, 52.25, 52.13, 31.98, 22.92.
J . Am. Chem. SOC.,Vol. 109, No. 18, 1987
545 i
Biphenyl Carbinol Malonates 16a and 16b. To a stirred solution of 320 mg (0.62 mmol) of the allyl protected biaryl diester 15a [Rf0.52, hexane:ethyl acetate (1:1)] in 10 mL of 10% aqueous ethanol was added 15 mg (0.13 mmol) of diazabicyclo[2.2.2]octaneand 40 mg (0.04 mmol) of tris(triphenylphosphine)rhodium(I) chloride. The resultant suspension was refluxed for 3 h and then poured into 10 mL of water. This mixture was extracted with ether (2 X 50 mL), the combined organic layers were washed with brine (50 mL), dried (MgS04), and filtered, and the solvent was evaporated to afford a dark brown gum. The gum was dissolved in ethyl acetate and filtered through a I-in. silica plug and the solvent evaporated to afford a brown oil. This was dissolved in I O mL of 10%' aqueous acetone and then 171 mg (0.63 mmol) of HgCI, added to the stirred mixture. A mixture of 180 mg (0.83 mmol) of yellow HgO in 10 mL of 10% aqueous ethanol was added to the mixture and the resultant orange suspension allowed to stir for 18 h at room temperature. The orange mixture was filtered through a Celite plug and the acetone evaporated. The residue was dissolved in ether (75 mL), rinsed with a saturated KI solution (2 X 25 mL) and brine (25 mL). dried (MgSO,), and filtered and the solvent evaporated to afford a dark yellow oil which was flash chromatographed [hexane:ethyl acetate ( 1 : I ) ] to afford 246 mg (83%) of 16a as a light yellow foam [Rf0.29, hexane:ethyl acetate (l:l)]: mp 47-49 "C; +27.5' (c 1.2, THF): IR (film) 3640-3280, 3010,2950,2930,2900,2840, 1760, 1740, 1730, 1597, 1568, 1500, 1480, 1455, 1435, 1400, 1343, 1225, 1140, 1105, 1035, 930, 750 cm-I; ' H N M R (270 MHz, CDCI,) 6 7.16 ( I H, s), 6.56 ( 1 H, s), 6.52 ( 1 H, s ) , 6.00 (1 H, d, J = 1.3 Hz), 5.98 ( 1 H , d, J = 1.3 Hz), 4.37 ( 1 H, q, J = 6.3 Hz), 3.87 (3 H, s), 3.86 (3 H, s), 3.67 (3 H, s), 3.63 (3 H, s). 3.56 (3 H, s), 3.51 ( I H, apparent dd, J = 8.1, 8.0 Hz), 3.24 ( I H, br s, exchanges with D,O). 3.08 (1 H, dd, J = 14.4, 8.1 Hz,) 2.91 ( I H, dd, J = 14.4, 8.0 Hz), 1.34 (3 H, d, J = 6.3 Hz); I3C N M R (67.9 MHz, CDCI,) 6 169.44, 152.95, 152.10, 147.82, 146.50, 141.37, 139.68, 131.48, 127.47, 126.78, 109.65, 108.79, 106.33, 101.15, 66.68, 60.88, 60.71, 56.27, 52.58, 51.88, 32.43, 24.24. Anal. Calcd for C24H28010:C, 60.49; H, 5.92. Found: C, 59.55; H, 5.63. Similar treatment of 296 mg (0.57 mmol) of the protected a1141 biaryl diester 15b [R,0.58, hexane:ethyl acetate (1:1)] as described for 15a afforded 226 mg (83%) of 16b as a light yellow glass following flash +13.6' (c chroamtography [Rf0,23, hexane:ethyl acetate ( l : l ) ] : 2.0, THF); IR (film) 3660-3200, 3070, 3020, 2970, 2950, 2895, 2840, 1750, 1735, 1595, 1477, 1398, 1342, 1228, 1137, 1100, 1054, 1030, 922, 807 cm-'; 'H N M R (270 MHz, CDCI,) 6 7.12 (1 H , s), 6.62 (1 H, s), 6 . 5 9 ( 1 H , s ) , 6 . 0 3 ( 1 H , d , J = 1 . 3 H z ) , 6 . 0 1 (1 H , d , J = 1 . 3 H z ) , 4 . 3 9 (1 H, q, J = 6.4 Hz), 3.89 (3 H, s), 3.87 (3 H, s), 3.64 (3 H, s), 3.62 (3 H, s), 3.53 (3 H, s), 3.27 (1 H, dd, J = 9.5, 6.4 Hz), 3.21 ( 1 H, br s, exchanges with D,O), 3.08 (1 H, dd, J = 14.2, 6.4 Hz), 2.89 ( 1 H. dd, J = 14.2, 9.5 Hz), 1.40 (3 H, d, J = 6.4 Hz); 13C K M R (67.9 MHz. CDCI,) 6 168.79, 152.73, 150.93, 147.77, 146.718 141.32, 138.24, 131.69, 127.36, 109.71, 105.90, 101.04, 67.63, 66.26, 60.91, 60.71, 56.00, 52.14, 51.72, 32.22, 25.46, 21.66. Anal. Calcd for C24H28010: C, 60.49: H, 5.92. Found: C, 59.50; H, 5.73. Dibenzocyclooctanone (19). To a stirred mixture of 9 mg (0.1 1 mmol) of sodium acetate and 104 mg (0.48 mmol) of pyridinium chlorochromate in 10 mL of dry dichloromethane at room temperature was added 100 mg (0.21 mmol) of the biaryl alcohol 16a [Rf0.29, hexane: ethyl acetate (1:l)J in 10 mL of dry dichloromethane. The mixture was stirred for 2 h and then poured into 10 mL of water. This was extracted with dichloromethane (2 X 25 mL), washed with brine (IO mL), dried (MgSO,), and filtered and the solvent evaporated to afford a dark brown gum, 17. This was dissolved in ethyl acetate and filtered through a I-in. silica plug and the ethyl acetate evaporated to afford a yellow oil. The yellow oil was dissolved in 10 mL of dry dichloromethane and 8 FL of trifluoroacetic acid was added to the stirred solution. Then 74 mg (0.23 mmol) of pyridinium bromide perbromide was slowly added over a I - h period. The organic solution was stirred for an additional 0.5 h, washed with aqueous NaHCO, (5 mL), 10% HCI (5 mL), and brine (5 mL). dried (MgSO,), and filtered and the solvent evaporated to yield a yellow solid, 18, which was dissolved in ethyl acetate and filtered through a I-in silica plug. The solvent was evaporated to afford a light yellow solid which was dissolved in 1 mL of dry T H F and added to a stirred mixture of 31 mg (0.27 mmol) of potassium tert-butoxide in 5 mL of dry T H F under an argon atmosphere at ambient temperature. The mixture was stirried for 0.5 h and the mixture acidified with concentrated HCI. The reaction mixture was extracted with ethyl acetate (2 X 50 mL), washed with brine (25 mL), dried (MgSO,), and filtered and the solvent evaporated to afford a dark yellow oil that was flash chromatographed [hexane:ethyl acetate (1:1)] to afford 53 rng (54%) of 19 [Rf0.35, hexane:ethyl acetate (1:1)] as a light yellow oil: -62.4' (c 2.6. THF); ' H N M R (270 MHz, CDCI,) 6 7.56 ( 1 H, s), 6.64 (1 H. s), 6.44 (1 H, s), 6.08 (1 H, s), 6.05 (1 H, s), 3.91 (3 H, s), 3.85 (3 H , s), 3.79 (3 H, s), 3.74 (3 H , s), 3.56 (3 H , s), 3.32 (1 H, d, J = 13.8 Hz), 3.20 ( I H,
5452
J . Am. Chem. SOC.1987, 109, 5452-5456
d, J = 13.8 Hz), 3.07 (1 H, d, J = 13.8 Hz), 2.76 (1 H, d, J = 13.8 Hz); "C NMR (67.9 MHz, CDC1,) 6 196.34, 170.65, 170.28, 153.63, 151.86, 151.15, 147.97, 142.32, 132.75, 132.54, 130.64, 128.00, 112.57, 108.97, 108.24, 102.10, 61.19, 61.03, 59.18, 56.22, 52.99, 52.89, 45.37, 36.50. Similar treatment of 164 mg (0.34 mmol) of biaryl alcohol 16b [R, 0.23, hexane:ethyl acetate (1:1)] as described for 16a afforded 82 mg (51%) of 19 as a light yellow oil that had identical physical properties. Dibenzocyclooctanone Carboxylates 20 and 21. To a stirred solution of 5 mL of 2.7 M KOH and 5 mL of ethanol was added a solution of 72 mg (0.15 mmol) of the biaryl diester 19 in 2 mL of ethanol and the resultant solution was refluxed for 2 h under argon. The solution was cooled to ambient temperature and the aqueous layer washed with ether (2 mL). The aqueous layer was acidified with concentrated HCl and this mixture extracted with ethyl acetate (2 X 20 mL), washed with brine (20 mL), dried (MgS04), and filtered and the solvent evaporated to afford the crude diacid. This was heated to 205 'C under argon in a Kugelrohr oven for 15 min and then cooled to ambient temperature. The residue was esterified with excess diazomethane in ether (20 mL) to afford a 1:l mixture of diasteromers (20, 21) which were separated by flash chromatography [hexane:ethyl acetate (1:1)] to yield 18 mg (29%) of 20 [RJ 0.35, hexaxethyl acetate (1: l)] which was recrystallized from methanol to afford white prisms followed by 19 mg (30%) of 21 [R,0.27, hexane:ethyl acetate (1:1)] as a clear glass. 20: mp 133-134 'C; [a]589+5.2' (c 1.7, THF); 'H NMR (270 MHz, CDC13) 6 7.69 (1 H, s), 6.67 (1 H, s ) , 6.47 ( 1 H, s), 6.08 (1 H, s), 6.05 (1 H , s), 3.92 (3 H , s), 3.86 (3 H, s), 3.72 (3 H, s ) , 3.58 (3 H, s), 3.17-3.12 (1 H, m), 3.07-2.93 (1 H , m), 2.84-2.76 (2 H, m), 2.66-2.56 (1 H, m); "C NMR (67.9 MHz, CDCI3) 6 198.03, 173.77, 153.69, 151.62, 151.26, 147.93, 142.11, 133.50, 132.27, 131.33, 127.99, 113.25, 108.76, 108.54, 102.15, 61.29, 61.05, 56.28, 51.10, 43.63, 41.47, 33.33. 21: [a1589 -3.1' (C 1.3, THF); 'H NMR (270 MHz, CDCI,) 6 7.53 (1 H, s), 6.63 (1 H, s), 6.55 ( 1 H , s), 6.07 (1 H, d, J = 1.0 Hz), 6.04 (1 H, d, J = 1.0 Hz), 3.91 (6 H, s), 3.69 (3 H, s ) , 3.57 (3 H, s), 2.91-2.80 (4 H, m), 2.49-2.43 (1 H, m);I3C NMR (67.9 MHz, CDC1,) 6 197.93, 173.77, 154.11, 152.00, 150.85, 147.87, 141.95, 133.23, 132.12, 127.84, 112.25, 109.08, 108.76, 107.38, 102.05,61.24,61.08, 56.43, 52.10, 45.07, 42.37, 33.85.
Interconversion of 21 to 20. According to the previous observat i o n ~ , ~ ~pure , ' ~ '21 ~ was heated for 12 h in xylene to give a 1:l mixture of 20 and 21 which was separated by flash chromatography as above. (-)-Steganone (1). To a stirred solution of 70 mg (0.17 mmol) of monoester 20 [Rf0.35, hexane:ethyl acetate ( l : l ) ] was added 1 mL of 5% KOH and 0.3 mL of 37% formaldehyde and the resultant clear solution stirred for 2 h at ambient temperature. The solution was then acidified with 3 N HCl and extracted with chloroform (3 X 20 mL), dried (MgSO,), and filtered and the solvent evaporated to afford a light yellow oil. The oil was dissolved in acetone (3 mL) and cooled to 0 'C and Jones reagent added slowly to the stirred solution until the orange color persisted. MeOH was added followed by water (5 mL) and this mixture extracted with CHCI, (3 X 10 mL). The combined organic layers were washed with 1 N NaOH (5 mL), dried (MgSO.,), and filtered and the solvent removed to afford a clear yellow oil. Flash chromatography [hexane:ethyl acetate (1:1)] afforded 14 mg (20%) of a clear oil that was recrystallized from methanol to afford 8 rng (1 1%) of (-)&eganone (1): mp 161-163 'C [lit. mp 155-156 0C,4 155-158 oC,6a 155.5-157 oC,6b154-156 0C6c];[.ID -161' ( e 0.8, CHCI,) [lit. [.ID -202' (C 0.76, CHC13),4[&'ID -191' ( C 0.76, CHC1,),6a [.ID -197' ( C 0.77, CHC16),6b[a]D -140' (C 1.16, CHC13)6']: 'H NMR (270 MHz, CDCI,) 7.53 (1 H,s), 6.63 (1 H, s), 6.54 (1 H, s ) , 6.11 (1 H, d , J = 1.3 H z ) , 6 . 0 9 ( 1 H , d , J = 1.3Hz),4.48(1 H , a p p a r e n t t , J = 9 . 7 H z ) , 4 . 3 7 (1 H, dd, J = 9.3, 7.0 Hz), 3.89 (3 H, s), 3.88 (3 H, s), 3.61 (3 H, s), 3.26-3.09 (2 H, complex m),2.84-2.76 (2 H, m); I3C NMR (67.9 MHz, CDCI,) 6 195.39, 175.89, 154.38, 152.16, 151.62, 148.14, 141.95, 133.76, 132.28, 131.99, 127.10, 112.83, 108.81, 108.11, 102.36, 67.05, 61.13, 56.38, 50.14, 44.96, 30.48.
Acknowledgment. W e a r e grateful to Professor Frederick Ziegler (Yale University) for providing us with spectral d a t a of (+)-steganone for comparison and the National Institutes of Health for supporting this study. W e also thank D r . James Fry of the CSU Regional NMR Center for assistance with high-field (360 and 500 M H z ) NMR spectra and Dr. Richard Himmelsbach for some preliminary experiments.
Polynitro-Substituted Strained-Ring Compounds, Synthesis, Mechanism of Formation, and Structure of trans-Dinitrocyclopropanes Peter A. Wade,*+William P. Dailey,t and Patrick J. Carrollf Contribution f r o m the Department of Chemistry, Drexel University, Philadelphia, Pennsylvania 19104, and the Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104. Received February 23, 1987 Abstract: 1,2-Dinitrocyclopropane,1,2-dimethyl- 1,2-dinitrocyclopropane,and 1,2-diethyl- 1,2-dinitrocyclopropane have been prepared in 23-36% yield by oxidative cyclization of the corresponding open-chain 1,3-dinitronate dianions with iodine in DMSO. In each case only the trans isomer of the dinitrocyclopropane was obtained. Treatment of 2,4-dibromo-2,4-dinitropentane with the lithium salt of 2-nitropropane gave trans-1,2-dimethyl-1,2-dinitrocyclopropane, suggesting the intermediacy of a halonitro nitronate intermediate in the oxidative cyclization process. Further mechanistic studies using m-dinitrobenzene suggest either an internal single-electron transfer, nonchain pathway or an internal SN2 process leading to the dinitrocyclopropanes. An X-ray crystallographic study performed on trans- 1,2-dinitrocyclopropane indicates substantially shortened distal C-C bonds (1.47 A) and bisected conformations for each nitro group. Ab initio calculations using a 4-31G basis set are in agreement with the X-ray data, except longer distal C-C bonds (1.49 A) are calculated. Ab initio calculations using a variety of basis sets were performed on nitrocyclopropane as a model.
Strained-ring compounds substituted with multiple nitro groups a r e of interest a s potential new high-energy materials and as compounds that might possess unusual chemical reactivity. Several such compounds have recently been synthesized,' typically in milligram quantities. T h e simplest strained-ring nitro compound, nitrocyclopropane,2 a n d a number of its simple analogues have long been known. However, dinitrocyclopropanes, except for one Drexel University. *Universityof Pennsylvania. 0002-7863/87/ 1509-5452$01.50/0
brief report3 on l,l-dimethyl-2,3-dinitrocyclopropanewhich we became aware of after this study was in progress, have not been discussed in t h e literature. Since dinitrocyclopropanes a r e the simplest example of strained-ring polynitro compounds, their (1) (a) Eaton, P. E.; Ravi Shankar, B. K.; Price, G. D.; Pluth, J. J.; Gilbert, E. E.; Alster, J.; Sandus, 0. J . Org. Chem. 1984, 49, 185. (b) Paquette, L. A,; Fischer, J. W.; Engel, P. Ibid. 1985,50, 2524. (c) Marchand, A. P.;Suri, S. C. Ibid. 1984, 49,2041. (d) Marchand, A. P.; Reddy, D. S. Ibid. 1984, 49,4078. (2) Haw, H. B.; Shechter, H. J . Am. Chem. SOC.1953, 75, 1382. (3) Brown, W. G.; Greenberg, F. H. J . Org. Chem. 1966, 31, 394.
0 1987 American Chemical Society
